Neurological disorders are diseases that affect the central nervous system (brain and spinal cord), the peripheral nervous system (peripheral nerves and cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous systems). More than 600 neurological diseases have been identified in humans, which together affect all functions of the body, including coordination, communication, memory, learning, eating, and in some cases mortality.
Although many tissues and organs in animals are capable of self-repair, generally the neurological system is not. Therefore, neurological disorders are often characterised by a progressive worsening of symptoms, beginning with minor problems that allow detection and diagnosis, but becoming steadily more severe—sometimes resulting in the death of the affected individual. While the exact causes or triggers of many neurological disorders are still unknown, for others the causes are well documented and researched. For some of these diseases there are “effective” treatments, which alleviate symptoms and/or prolong survival. However, despite intense research efforts, for most neurological disorders, and particularly for the most serious diseases, there are still no cures. Hence, there is a clear need for new therapeutics and treatments for neurological disorders.
Current knowledge of neurological disorders shows that they can be caused by many different factors, including (but not limited to): inherited genetic abnormalities, problems in the immune system, injury to the brain or nervous system, or diabetes. One known cause of neurological disorder is a genetic abnormality leading to the pathological expansion of CAG repeats on certain genes, which results in extended polyglutamine (polyQ) tracts in the expressed mutated gene products (Walker (2007) Lancet 369(9557): 218-228). The resulting proteins are thought to aggregate and cause toxic gain-of-function diseases, including spinocerebellar ataxias, spinobulbar muscular atrophy and Huntington's disease (HD; Orr & Zoghbi (2007) Annu. Rev. Neurosci. 30: 575-621; Cha (2007) Prog. Neurobiol. 83(4): 228-248). HD neuropathology is associated with selective neuronal cell death, primarily of medium spiny neurons of the caudate and putamen, and to a lesser extent cortical neurons, leading to cognitive dysfunction and chorea (Walker (2007) Lancet 369(9557): 218-228; and Kumar et al. Pharmacol. Rep. 62(1): 1-14). Since the discovery, in 1993, that the htt gene caused HD (The-Huntington's-Disease-Collaborative-Research-Group (1993) Cell 72(6): 971-983), much attention has focused on how the CAG-repeat number affects the pathology and progression of this disease. Normally, the number of CAG repeats in the wild-type htt gene ranges from 10 to 29 (with a median of 18), whereas in HD patients it is typically in the range of 36 to 121 (with a median of 44). Furthermore, it has been shown that the age of onset of HD disease is correlated to CAG repeat number (Walker (2007) Lancet 369(9557): 218-228; and Kumar et al. Pharmacol. Rep. 62(1): 1-14).
Although there has been a great deal of research into cures for HD disease, currently available therapeutics treat only the symptoms of the disease, and so there is still no way of stopping or delaying the onset or progression of HD (Walker (2007) Lancet 369(9557): 218-228; and Kumar et al. Pharmacol. Rep. 62(1): 1-14). For this reason it would be extremely desirable to have a treatment for HD disease that addresses the cause rather than the symptoms of the disease.
Recently, RNA interference (RNAi) was shown to reduce expression of mutant htt (van Bilsen et al. (2008) Hum. Gene Ther. 19(7): 710-719; Zhang et al. (2009) J. Neurochem. 108(1): 82-90; Pfister et al. (2009) Curr. Biol. 19(9): 774-778). Although RNAi has been shown to be a very powerful tool, the success of this technique depends on targeting single nucleotide or deletion polymorphisms that differentiate between mutant and wt alleles, and these often differ from patient to patient. The apparent requirement for personalised siRNA designs currently raises challenges for clinical trials and approved use in humans.
In a more general approach, Hu et al. used peptide nucleic acid (PNA) and locked nucleic acid (LNA) antisense oligomers, to target expanded CAG repeats of the ataxin-3 and htt genes (Hu et al. (2009) Nat. Biotechnol. 27(5): 478-484; Hu et al. (2009) Ann. NY Acad. Sci. 1175: 24-31). They reported selective inhibition of the mutant allele with peptide nucleic acids (PNAs) for up to 22 days. Although these results were promising, PNAs cannot be delivered to the central nervous system. Therefore, the authors also tried locked nucleic acids (LNAs), which are perhaps more suitable for use in vivo. Although selective inhibition of the mutant allele was observed, only up to 30% inhibition of wt htt was seen at the highest and most effective concentration of LNA used.
Therefore, it would be highly desirable to have alternative and/or more effective therapeutic molecules and treatments for HD and related disorders caused by expanded CAG repeats.
Accordingly, the present invention seeks to overcome or at least alleviate one or more of the problems in the prior art.